Trends in endpoint use in pivotal trials and efficacy for US Food and Drug Administration–approved solid tumor therapies, 1995-2021

BACKGROUND: Many cancer therapies are now approved based on surrogate endpoints such as progression-free survival (PFS) to ensure that patients have speedy access to life-saving cancer medicines. However, the link between surrogate endpoints and overall survival (OS) is not well established in many cancers. OBJECTIVE: To characterize trends in endpoints used in pivotal trials leading to approval for US Food and Drug Administration (FDA)–approved solid tumor therapies and their efficacy from 1995 to 2021. METHODS: We reviewed the FDA Oncology (Cancer)/Hematologic Malignancies Approval Notifications webpage to extract data on median OS and PFS among solid tumor therapy approvals from 1995 to 2021. We summarized trends in percentage of trials reporting OS vs PFS, median OS and PFS, and trial designs. We conducted subgroup analyses for lung and breast cancer therapies. RESULTS: Median OS was reported more frequently until 2010 to 2012, when median PFS and OS were reported in 65.2% and 60.9% of trials, respectively. Between 1995 and 2021, there were no observable trends in median OS over time for solid tumor therapy approvals. Median PFS increased by 3.0 months over time. For lung cancer therapies, median OS increased by 6.8 months between the time periods of 1998-2000 and 2019-2021, whereas median PFS increased by 5.0 months between the time periods of 2007-2009 and 2019-2021. For breast cancer therapy, median OS slightly decreased over time, whereas median PFS has increased by 3.4 months since 1995. There has been a recent shift in use of single-arm trials leading to oncology drug approvals. CONCLUSIONS: There has been a transition from reporting OS to PFS, and median PFS has increased by 3 months while median OS has remained stable. The different trends in overall and progression-free survival highlights the challenge and importance of measuring the value of oncology drugs.


Plain language summary
We reviewed cancer therapies for solid tumors approved by the US Food and Drug Administration between 1995 and 2021. We found that there was a shift toward the use of surrogate endpoints and single-armed trials over time. Progression-free survival has increased by 3 months and overall survival has remained stable over this time period.

Implications for managed care pharmacy
There has been a shift toward use of surrogate endpoints and interim results in oncology trials. Efficacy appeared to be increasing when measured using a surrogate endpoint but remained stable when measured using overall survival. The different trends in overall and progression-free survival highlights the challenge and importance of measuring the value of oncology drugs.
Over the past 2 decades, the number of cancer treatments in development has increased, with some therapies proving to be highly effective. 1,2 The cost of cancer therapy is high and increasing. 2 Howard et al found that the average launch price of anticancer drugs, adjusted for inflation and health benefits, increased by 10% annually, or about $8,500 per year from 1997 to 2013. 3 Factors contributing to the high price include the necessity of long follow-up to determine overall survival (OS) and large sample size requirements. 4 The use of progression-free survival (PFS) as a surrogate endpoint can significantly shorten the length of time to US Food and Drug Administration (FDA) approval and ultimately help bring life-saving cancer treatments to market quicker. 5 However, there have been examples of approvals that have failed to establish a link between the use of surrogate endpoints and OS. 6 By using these therapies, patients may miss the best window of opportunity for treatment. The objective of this study was to summarize the trends in the endpoints used in the clinical trials leading to approval of solid tumor cancer therapies and their efficacy over the past 2 decades.

Methods
The FDA Oncology (Cancer)/Hematologic Malignancies Approval Notifications webpage was used to identify solid tumor oncology therapies (drug-indication pairs) approved from December 27, 1995, to March 10, 2021. 7,8 Therapies for nonsolid tumors, combination regimens, and treatments solely indicated for cancer-related symptoms or treatment side effects were excluded. Study and drug characteristics were extracted from the FDA webpage and pivotal clinical trials that led to FDA approval. Drug-indication pairs were classified based on the following: brand/generic name, indication, line of therapy, approval date, and route of administration. Descriptive statistical analysis was conducted using Statistical Package for Social Sciences software (SPSS, IBM Corp.) version 26. The unit of analysis was drug-indication. Trial characteristics were summarized as frequencies for categorical variables and as means with SDs for continuous variables. We included all solidtumor therapies in the primary analysis. We also performed subgroup analysis on lung and breast cancer approvals, as most approvals were for these cancer types during the studied time period. Given that this project did not involve research on human subjects and was an exploratory analysis from published literature and data, it was exempt from the Institutional Review Board's review by the University of Texas MD Anderson Cancer Center.

Results
Between January 1995 and March 2021, a total of 251 cancer drug-indications met our eligibility criteria. Baseline characteristics of pivotal trials of included cancer drugindications are summarized in Table 1. The most common cancer sites in the sample were lung (22.3%), breast (16.7%), skin (8.4%), and colorectal (6.8%). More than half (54.2%) of the therapies were investigated in trials that included an active comparator, and 24.7% and 18.7% were placebo-controlled and single-arm trials, respectively. Approximately one-third (32.7%) of therapies were approved for first-line treatment, and the rest of approvals were for second-line treatment and beyond or not specified. The route of administration for the approvals was evenly split between intravenous and oral, 49% and 48.2%, respectively.  Figure 2).
From the 1995-1997 to 2019-2021 time frames, mean OS for all approvals has stayed consistent. The mean PFS in all approvals between these time periods has increased noticeably, from 4.5 ± 1.9 months in 1995-1997 to 8.9 ± 6.9 months in 2019-2021 ( Figure 1). In subgroup analysis, the mean OS for lung cancer approvals increased from 8. This transition from trials using OS to PFS as a primary endpoint is reflective of the increasing number of approvals through the FDA's Accelerated Approval program, where surrogate endpoints such as PFS are used to demonstrate efficacy. 8,9 The FDA developed its Accelerated Approval Program to allow for earlier approvals for medications that treat serious conditions or fill an unmet need. 5,10 Because data are not fully mature at the time of Accelerated Approval, confirmatory trials are usually required to confirm the From 1995 to 2015, active comparator-controlled trials were always the majority among trials leading up to FDA approval (Supplementary Figure 3). After 2015, the percentage of active comparator-controlled trials decreased, and the percentages of single-arm and placebo-controlled trials increased. Active comparatorcontrolled trials made up a mere 21.4% of studies in 2019-2021. In the period between 2013 and 2021, the use of single-arm trials grew from 2.6% up to 40%.

Discussion
To our knowledge, this is the first study to characterize the trends in OS and PFS reporting for all solid tumor therapies approved since 1995. These findings suggest that over time, there has been a transition from trials using OS to PFS as a primary endpoint in oncology drug approvals, and this

LIMITATIONS
This study has several limitations. Analysis was descriptive and did not adjust for the stage of cancer for which the drug is indicated. Owing to the sample size limitation, we were not able to examine individual cancer sites except for lung and breast. In addition, our study focused solely on solid tumor therapies, as incidence and patient prognosis varies when compared with nonsolid tumor therapies. 1 Further research should explore similar trends in nonsolid tumor therapies to gain a better understanding of the improvements in efficacy of all types of cancers.

Conclusions
The number of FDA-approved solid tumor therapies steadily increased from 1995 to 2021. With that increase, a transition from reporting OS as an efficacy endpoint to PFS was seen, as was a shift in trial design from mainly active comparator-controlled trials to a notable increase in singlearmed studies. From 1995 to 2021, the average median OS of FDA-approved solid tumor therapies did not change substantially, whereas the average median PFS increased by approximately 3 months. Subgroup analysis revealed that lung and breast cancers had the most approvals during the study period, with varying trends in outcomes.

DISCLOSURES
Dr Suh reports personal fees from Bayer US LLC.
anticipated clinical benefit. This can be concerning, as many cancer drugs approved via the FDA's Accelerated Approval pathway were later shown to have varied benefits in OS reported in confirmatory trials. 11 There is added concern when considering that there has been an increase in therapies receiving FDA's Accelerated Approval based on single-arm trials, despite the existence of promising therapies through the regular approval pathway, highlighted by our study as well as Ribeiro et al. 9 Lung cancer and breast cancer have seen the largest number of new approvals in recent years. The Lung Cancer Research Foundation also notes the exponential increase in new drug approvals for the disease and attributes this finding to the creation of targeted and immunotherapies. 12 Leo et al studied breast cancer approvals during the 70-year period from 1949 to 2018. 13 They also found that the rate of new drug approvals dramatically increased and contribute these findings in part to the development of targeted therapies. 13 These findings match the acceleration of new drug approvals seen across all fields of oncology. 9,14,15 The goal in analyzing these trends was to understand if new agents had better efficacy. We found that from 1995-1997 to 2019-2021, average OS stayed consistent. The average PFS between these time periods has increased noticeably, from 4.5 ± 1.9 months in 1995-1997 to 8.9 ± 6.9 months in 2019-2021. A 2017 study by Salas-Vega et al demonstrated similar findings with regard to OS. The investigators evaluated the comparative therapeutic value of all new cancer medications approved by the FDA and the European Medicines Agency between 2003 and 2013. Of the 53 new molecular entities studied, 43% increased OS by 3 months or longer, 11% increased OS by less than